???? PROJECT SUMMARY / ABSTRACT ??????????????????????????????????????????????????????? Millions of Americans abuse illicit drugs, including the stimulant cocaine. The annual economic burden this creates is in the hundreds of billions of dollars. There is a substantial genetic contribution to the development of substance abuse disorders (SUD), but many molecular pathways remain to be elucidated. The vinegar fly, Drosophila melanogaster, has been a genetic model organism for more than a hundred years. Major strides have been made in the last 10 years studying the behavioral responses to alcohol in flies, both in characterizing novel conserved genes and pathways, but also in the development of new assays that resemble addiction more closely. The goal of this proposal is to engineer Drosophila flies to self-administer cocaine. This compound normally acts as an aversive antiherbivore chemical, and we hypothesize that this is because cocaine amplifies dopaminergic signaling, which in flies is mainly, but not exclusively, aversive. First, we will determine whether flies self-administer cocaine. We will establish dose response curves, and test the effects of cocaine pre-exposure on cocaine preference/aversion. We will also test the impact of dopamine signaling on cocaine consumption. Second, we will engineer flies that contain cocaine-sensitive dopamine transporters only in these dopamine neurons required for the development of self-administration. In the other, aversive dopamine neurons, these engineered flies will contain a cocaine-insensitive dopamine transporter. The proposed experiments will yield a novel cocaine self-administration assay in a model organism that has historically demonstrated great economy of scale and success in elucidating the molecular mechanisms of numerous basic physiological, and behavioral processes.